Multiple roles for bone morphogenetic protein-4 in neural development

Abstract

Members of the bone morphogenetic protein (BMP) family are among the most widely distributed and important regulators of animal development. BMPs and their receptors are expressed in the embryonic nervous system, and several roles for BMPs in early neural development are described. BMP expression continues in a dynamic fashion during later neural development and into adulthood, however, suggesting that BMPs are not limited to the regulation of early neural development. This thesis constitutes an analysis of BMP functions in the nervous system during later embryogenesis, focusing on three distinct systems. In the first, BMPs are postulated to promote astroglial differentiation in the forebrain. We test this hypothesis through the analysis of novel transgenic mice engineered to overexpress BMP4 during forebrain development. We demonstrate that BMPs do promote astroglial differentiation in vivo. We further show that this increase in astroglia comes at the expense of oligodendroglial differentiation, suggesting that BMPs act through a direct instructive effect on multipotential neural stem cells. Our second experimental series examines the importance of BMPs to maturation of sympathetic neuroblasts in the peripheral nervous system. Using a tissue culture system, we show that BMPs both inhibit proliferation of sympathetic neuroblasts and promote the acquisition of mature neuronal traits including neurotrophin dependence. We further show that these BMP effects are mechanistically distinct, with divergent requirements for the intracellular mediators p21 and Msx-2. Finally, we turn to development of dorsal root ganglion (DRG) sensory neurons, for which previous tissue culture studies have implicated BMPs in the regulation of neuropeptide expression, among other effects. To test the hypothesis that BMPs play a critical role in DRG neuron development, we utilized a novel transgenic mouse system in which the epidermis, a DRG target tissue, overexpresses BMP4. In contrast to prior studies, we find that BMP4 does not significantly affect neuropeptide expression. Instead, we demonstrate that BMP4 modulates the number and structural properties of adult sensory neurons. Taken together, our results confirm multiple roles for BMPs in neural development and open new avenues for the further investigation of BMP function.